CN1607941A - Pharmaceutical compositions in particulate form - Google Patents
Pharmaceutical compositions in particulate form Download PDFInfo
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- CN1607941A CN1607941A CNA028260074A CN02826007A CN1607941A CN 1607941 A CN1607941 A CN 1607941A CN A028260074 A CNA028260074 A CN A028260074A CN 02826007 A CN02826007 A CN 02826007A CN 1607941 A CN1607941 A CN 1607941A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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Abstract
A method of preparing a pharmaceutical composition is described, comprising 1) atomizing a liquid formulation of a therapeutic agent to produce an atomized formulation; 2) freezing said atomized formulation to form solid particles; and 3) drying said solid particles at about atmospheric pressure to produce a powder, wherein said drying is performed in the presence of vibration, internals, mechanical stirring, or a combination thereof. Another method is described, comprising 1) atomizing a liquid formulation of a therapeutic agent to produce an atomized formulation; 2) freezing said atomized formulation to form solid particles; and 3) drying said solid particles to produce a powder; wherein the atomized formulation comprises droplets having an average mean diameter of between about 35mu and about 300mu, and/or the powder comprises dried particles having an average mean diameter of between about 35mu and about 300mu. Compositions made by the above methods, and methods of using the compositions, are also described.
Description
The present invention require to be registered on October 22nd, 2002 the interim patent 60/419959 of the U.S., be registered in the interim patent 60/339156 of 11 days the U.S. of calendar year 2001 December and be registered in the priority of the interim patent 60/331952 of the U.S. in November 19 calendar year 2001, it is reference that every patent is all drawn at this with its complete content.
Invention field
The present invention relates to such as the method for preparing dry state granular (for example powdery) pharmaceutical composition.This compositions is fit to be applied to such as (for example carrying out intranasal administration) such as mucosal tissues.Introduced compositions prepared according to the methods of the invention and described compositions has been applied to patient's method.The example of the present composition comprises insulin and influenza vaccines, and described influenza vaccines contain the code nucleic acid of inactivated virus particle or influenza hemagglutinin.
Background of invention
The method that forms the dry state pharmaceutical composition has been seen in report.For instance, these methods comprise steps such as precipitation, spray drying and/or mechanical lapping dry.Some is reported method employing anhydrous solvent, makes the dampness rapid evaporation, thereby shortens the processing time.But such solvent can destroy just at exsiccant pharmaceutical reagent (for example protein).Often reunite easily with the granule that the method in the report forms, and/or lack the required suitable dimension of best medical usage, density (for example bulk density), form and/or stability.
Therefore, need to overcome the dry state preparation of drug combination method of above-mentioned one or more defectives.
Summary of the invention
The present patent application relates to such as preparation powdered drug method for compositions, is included under the situation about existing such as vibration component, internals, mechanical agitation member or this several situation combinations, near under the non-pressurized pressure described compositions is being carried out drying.In another embodiment, the present invention relates to the method such as preparation granular (for example powdery) pharmaceutical composition, wherein powder comprises the dried particles of the about 35-100 μ of average diameter m.Compositions and these method for compositions of use have also been introduced with method for preparing.
Brief description
Can more completely be familiar with various characteristics of the present invention and attendant advantages in conjunction with the accompanying drawings.
Figure 1A is depicted as spraying of the present invention-frozen gas drying equipment sketch map.
Figure 1B is depicted as the spraying-freeze-dried device sketch map of band vibration component and internals.
16.SFD chamber 36. pumps
2. spray nozzle 20. cooling systems
48. heating tape 44. bypass valves
12. solution (liquid) 46. by-pass lines
28. filter 18. atomizing airs
38. valve 49. vibration sources
32. air filter 50. internals
Figure 2 shows that the reaction of serum antibody (Ab) to the IN input of various influenza vaccines ingredients.
Figure 3 shows that mouse serum Ab is to carrying out the reaction of immunity with pFLU-HA.
Figure 4 shows that the particle size distribution of the liquid virion of the Accuspray nozzle generation of measuring with laser diffractometry.
Figure 5 shows that the gene expression of the liquid pCMC-LUC of input IN luciferase afterwards.
Figure 6 shows that the gene expression of the luciferase of mouse behind the input IN pCMV-LUC.
Figure 7 shows that the serum Ab titre of carrying out after the pFLU-HA immunity.
Figure 8 shows that with the Accuspray nozzle ejection and by the scanning electron microscope (SEM) of the exsiccant SFD insulin of lyophilization and scheme.
Figure 9 shows that scanning electron microscope (SEM) figure of the SFD insulin among Fig. 8, but amplification is bigger.
Figure 10 shows that in SFD and the liquid insulin sample detection to amide (chemical degradation), detection be stability.
Figure 11 shows that the dampness and the drying time of the compositions that produces with the lyophilization gas method.
| Gas flow rate, m/s ■ .219+.344 ◆ .469 ▲ .594 .719 * .844 o2.00 |
Figure 12 shows that the SEM image of the mannitol powder that produces with spray chilling gas drying method.
Figure 13 A is depicted as in the contrast that has and do not have the seroimmunity reaction of IN input SFD influenza vaccines under the situation of chitosan.
Figure 13 B is depicted as and is not having the 56th day the immunoreactive contrast of nasal mucosa behind the IN input SFD influenza vaccines under the situation of chitosan.
Figure 14 shows that moisture level (low dry gas flow velocity (.39m/s)) in not having the whole SFD method of vibration component and internals from vulcanizing the sample of collecting in bed top and bottom.
Figure 15 shows that from the granule SEM of fluid bed top formation sample in the time of 30 minutes.
Figure 16 shows that from the granule SEM of fluid bed top formation sample in the time of 60 minutes.
Figure 17 shows that permeability with two kinds of different exsiccant powder of gas velocity.Among the figure effect (V-FB-SFD) of flow velocity to the distillation time.
Figure 18 shows that the particle size distribution of mannitol particles freezing and that form by lyophilization by the Accuspray nozzle spray.Particle size distribution is passed through determination of laser diffraction.
Figure 19 shows that the sem photograph (SEM) of SFD purified insulin powder (than insulin/lactose moisture-proof gas more).
Figure 20 shows that SFD insulin/lactose composite powder is exposed to the SEM behind the normal temperature and pressure dampness.
Shown in Figure 21 is SD (spraying-drying) and SFD (spraying-freeze-dried) Sprinkle Caps after the capsule film rupture.Can't see the lactose that is retained in the SFD Sprinkle Caps.
Detailed Description Of The Invention
The present invention relates to such as granular (for example powdery) dry state preparation of drug combination method; Relate to compositions with these method preparations; Relate to method with these combination treatments patient.
One aspect of the present invention relates to the method for pharmaceutical compositions, and described method comprises following one or more step: nebulae inhalation disease or prophylactic liquid ingredients produce the atomizing ingredients; Freezing described atomizing ingredients forms solid granulates; Dry described solid granulates forms dried particles (for example powder).Described atomizing ingredients should comprise volume mean diameter (such as W.H.Finley in " suck pharmaceutical aerosol mechanics preliminary " definition, Academic Press, London, UK (2001)) between 35-300 μ m, more suitable droplet between about 50-300 μ m, and/or described powder comprises volume mean diameter between 35-300 μ m, more suitable dried particles between about 50-300 μ m.These droplets or particulate volume mean diameter are preferably between the 50-100 μ m.In a preferred embodiment, have an appointment at least 50% dried particles volume diameter average diameter about 80% within; Should have an appointment at least 50% dried particles volume diameter average diameter about 60% within.In a preferred implementation, described powder comprises average air power diameter (defining as W.H.Finley, the same) between about 8-140 μ m, should be between about 8-80 μ m, and more suitable dried particles between about 20-70 μ m.The method and compositions prepared by this method are called " spraying-freeze-dried " method or compositions at this.
The aforementioned pharmaceutical compositions granule has suitable dimensions, density and/or form, so that by the nose administration.Do not want to be bound by any particular theory, the present invention proposes following mechanism: after above-mentioned composition enters intranasal, just be sent to intranasal mucosa or nasal sinuses mucosa, they are here adhered rather than are pulled to the hole chamber, enter pulmonary system, adhere to like this said composition is adsorbed at faster speed than other treatment disease or prophylactic compositions ingredients.When the present composition is vaccine, set up the therefore minimizing of required time of effective antibody response, mucosal immunity power (being media with the IgA reaction for example) strengthens.Drop into this vaccine of the present invention at intranasal, can cause system and nasal mucosa IgA immunoreation simultaneously.
The present invention provides a kind of method of pharmaceutical compositions on the other hand, and it comprises following one or more step: nebulae inhalation disease or prophylactic liquid ingredients produce the atomizing ingredients; Freezing described atomizing ingredients forms solid granulates; Under situation about existing,, form dried particles (for example forming powder) near dry described solid granulates under the normal pressure such as vibration component, internals, mechanical agitation member or this several situation combinations.Here " near normal pressure " refers to the atmospheric pressure of about 0.5-5.Here " drying " refers to remove the volatile component of ingredients from the solid frozen particle.Described powder should comprise volume mean diameter between 35-300 μ m, and is more suitable between about 50-300 μ m, is preferably in the dried particles between the 50-100 μ m; And/or the volume averaging aerodynamic diameter of dried particles is between about 8-140 μ m, should be between about 8-80 μ m, more suitable dried particles between about 20-70 μ m.In a preferred embodiment, have an appointment at least 50% dried particles volume diameter average diameter about 80% within; Preferably have at least about the volume diameter of 50% dried particles average diameter about 60% within.In dry run, the frozen solid granule is preferably the fluidisation attitude.The method and compositions prepared by this method are called " spraying-freezing-normal pressure-drying " method or compositions.The benefit of production compositions in this way is that they can not reunited.
Other advantages of the present composition are, described compositions easily forms aerosol, has good stable, aseptic and emission dosage, can keep biological activity well, left drug is few in explosive-feeding processing device such as inhalation device, and reconfigures in liquid easily.Described granule has low bulk density, and this helps granule to form aerosol, for example is used for the respiratory tract drug delivery.Described granule is very fine, and they are transported easily.The inventive method can be controlled particle size distribution well.Therefore, the particle size distribution of the present composition is subjected to good control.Particulate form has reduced the probability of they reunions, can also further help to form aerosol.It is stable that described compositions keeps under non-freezing conditions, thereby compare with liquid formulation, and they are more convenient aspect accumulating, more economical.The present composition is particularly suitable for the large-scale inoculation vaccine.In an embodiment of the invention, invention compositions is by respiratory system administration (for example intranasal administration).The present composition is particularly suitable for intranasal administration, makes accurate aiming nasal mucosa target become possibility because be subjected to the particle size distribution of good control.Compare with injection (for example Intradermal or subcutaneous injection), the advantage by the respiratory system administration comprises adaptability and the immunoreation that improves the patient.Another benefit by respiratory tract administration is that it is non-invasion procedure, and is painless, is convenient to operation.
Those skilled in the art knows the character of bulk density.Solid material pulverize, after the levigate or processing, every particulate real density is all identical, but the geometric space that material occupies is big.In other words, be spheric as fruit granule, then geometric density is less than real density, and is similar little by 50%.
In the carrying or vibration processes of dusty material, smaller particles can get in the space between the larger particles, and the shared geometric space of powder reduces, thereby its density increases.At last,, then can not make the further compacting of natural particle, so just obtain the largest particles accumulation if do not exert pressure.
Under the condition that accumulation rate, accumulation force (whereabouts) and drum diameter are controlled, the condition of maximum deposition efficiency is highly repeatably.The measuring method of this bulk density British Pharmacopoeia method " apparent volume ", ISO 787/11 and ASTM about standard method of test B527, the D1464 of bulk density and D4781 in standard to some extent.
The present invention provides the method for above-mentioned pharmaceutical compositions on the other hand, wherein freezing step be by the ingredients that will atomize introduce that temperature is lower than that the cold fluid of liquid formulation freezing point or medium carry out (used here term " fluid " had both comprised gas, as Compressed Gas, also comprise liquid); The boiling point of wherein said fluid or medium or sublimation point are lower than the boiling point or the sublimation point of atomizing ingredients; Wherein drying is being undertaken by methods such as dry freeze near (making up under the situation about existing such as vibration component, internals, mechanical agitation member or this several situations) under the normal pressure, and wherein freezing and drying should carried out (making up under the situation of existence such as vibration component, internals, mechanical agitation member or this several situations) near in the non-pressurized cold air; Wherein treating disease or preventative reagent is protein (for example insulin), nucleic acid or virion, wherein therapeutic agent is an immunoreagent, as influenza vaccines (for example comprising the particulate vaccine of deactivation influenza), subgroup influenza vaccines or nucleic acid coding influenza hemagglutinin protein, wherein hemagglutinin should be subjected to the control of structural priming, particularly strong structural priming is as the CMV promoter; Wherein liquid formulation also comprises pharmaceutical excipient, as mucoadhesive, and for example chitosan, dermatan sulfate, chrondroitin or pectin, perhaps liquid formulation mainly is made up of therapeutic agent and water.
The present invention provides the pharmaceutical composition with method for preparing on the other hand; The pharmaceutical composition that perhaps comprises dried particles, the volume mean diameter of wherein said dried particles are between 35-300 μ m, and be more suitable between about 50-300 μ m, is preferably between the 50-100 μ m; And/or the average air power diameter of dried particles is between about 8-140 μ m, should be between about 8-80 μ m, more suitable between about 20-70 μ m.Should have an appointment at least in the compositions 50% dried particles volume diameter average diameter about 80% within; The volume diameter of more suitable 50% the dried particles of having an appointment at least average diameter about 60% within.
The present invention provides a kind of patient's of treatment method on the other hand, and it comprises the pharmaceutical composition according to the inventive method preparation of using effective dose to the patient, and/or the pharmaceutical composition with aforesaid properties; Wherein said compositions by in the respiratory system, intranasal, internal rectum, intravaginal, Sublingual or parenteral administration, should pass through intranasal administration, and/or described delivery of composition is arrived nasal mucosa.The present invention provides the method that reduces treatment disease or preventative reagent dosage on the other hand, and described consumption is that this method comprises the pharmaceutical composition of the present invention of using effective dose by intranasal to the patient to the required dosage of generation curative effect behind patient's Nasacort.The present invention provides a kind of immunoreactive method that causes on the other hand in patient's body, comprise the immune composition of the present invention of using effective dose to the patient, and wherein said compositions is by intranasal administration, and/or described compositions is influenza vaccines of the present invention.
The present invention provides the method for pharmaceutical compositions on the other hand, it is included under the situation about existing such as vibration component, internals, mechanical agitation member or this several situation combinations, near dry solids under the normal pressure, described solid particle is that the atomizing ingredients by cold therapy disease or prophylactic liquid reagent forms.
The present invention provides the method for pharmaceutical compositions on the other hand, it comprises the liquid formulation that described treatment disease of atomizing or preventative reagent form, produce the atomizing ingredients, follow freezing described atomizing ingredients, form solid particle, dry described solid particle, obtain powder, wherein dried powder comprises average diameter between 35-300 μ m, and is more suitable between about 50-300 μ m, is preferably in the dried particles between the 50-100 μ m; Wherein have an appointment at least 50% dried particles volume diameter average diameter about 80% within; The volume averaging aerodynamic diameter of described dried particles is between about 8-140 μ m.
Any treatment disease or preventative reagent all can be used for the inventive method and compositions.Here used " therapeutic agent " (claims " active agents " here sometimes or API) can produce the compositions of curative effect after referring to use in cell, tissue, organ or patient's body.After being applied to the patient, the compositions that comprises one or more therapeutic agent can produce " clinical effectiveness ".Here used term " clinical effectiveness " refers to useful clinically biological respinse, is applicable to diagnosis and treatment simultaneously.For example, the present composition can be used in the diagnostic test method, and/or be used for treatment, prevention disease of patient and/or alleviate disease symptoms.
Therapeutic agent can be an any kind, for example comprises polypeptide (protein), polynucleotide (nucleic acid), micromolecule such as steroid and virion.Term polypeptide and protein here are used interchangeably, and term polynucleotide and nucleic acid also are like this.
Suitable polypeptide or peptide include, but is not limited to somatomedin, cytokine, antigen, antibody, interleukin, lymphokine, interferon, enzyme etc., include, but is not limited to anti-IgE antibodies, organize plasminogen activity factor (tPA), calcitonin, erythropoietin (EPO), factors IX, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), growth hormone (particularly human growth hormone), heparin (comprising the low-molecular-weight heparin), insulin, quasi-insulin growthing factor I (IGF-I) and II (IGF-II), interleukin, interferon-ALPHA, β and γ, Alfasone, releasing hormone, Somat and analog, vassopressin and analog, follicle stimulating hormone, dextrin, cilary neurotrophic factor, somatotropin releasing factor, insulinotropic hormone, hugely have a liking for colony-stimulating factor (M-CSF), nerve growth factor, parathyroid hormone, α-1 antitrypsin, anti-rsv antibodies, deoxyribonuclease, Her2, CFTR (gallbladder cystic fibrosis transmembrane conduction regulator gene product, be used for the treatment of gallbladder cystic fibrosis), insulin etc.In a preferred implementation, polypeptide is an insulin.Also can adopt polypeptide such as labelled protein.
In a preferred implementation, polypeptide can be indicated in the infectious substance or on the surface, as antibacterial, virus, protozoacide or other parasites, comprises malaria etc.This peptide species can be at central immunoreagents that is used as such as vaccines.
Polypeptide can be natural, also can be that reorganization forms, and can carry out modification with art-recognized any method, as each peptide species of discussing among the US2002/0052475.Be used for the fragment that polypeptide of the present invention can be a full length protein, the appropriate polypeptide of virtually any size (length) can adopt.For example, comprising the polypeptide of one or more epitopes and/or antigen sequence can be as causing immunoreactive reagent.
Suitable polynucleotide comprise the carrier that contains recombination sequence etc., and described recombination sequence is a therapeutic target polypeptides coding.These polynucleotide can be above-mentioned or other any therapeutical peptide codings.Clone these sequences, target sequence and suitable expression control sequenc are effectively coupled together the generation recombinant vector, these methods all are very conventional methods.Typical method is seen and is set forth in Sambrook, J. wait work (1989) " molecular cloning---laboratory manual " (Molecular Cloning, a Laboratory Manual), Cold SpringHarbor Press, Cold Spring Harbor, NY and Ausubel, work such as F.M. (1995) " existing test report in the molecular biology " (Current Protocols in Molecular Biology), NY, John Wiley﹠amp; Sons etc.Term " expression control sequenc " refers to regulate the polynucleotide sequence of expression of polypeptides, and polypeptide is encoded by realizing the polynucleotide that function (" effectively ") connects with it.Expression can be controlled at the level of mRNA or polypeptide.Therefore, expression control sequenc comprises element relevant with mRNA and the element relevant with protein.These elements comprise promoter, (virus or cell) enhancer, ribosome binding sequence, transcription terminator etc.If expression control sequenc can realize or strengthen the expression of coded sequence in the present position, show that then expression control sequenc effectively has been connected on the nucleotide coding sequence.For example, when enhancer effectively was connected to 5 ' of coded sequence, enhancer just can promote the expression of coded sequence.Suitable expression control sequenc as strong constitutive property or scalable enhancer, is conspicuous for those skilled in the art.
Polynucleotide can be natural, the generation of also can recombinating.Be used for the fragment that polynucleotide of the present invention can be total length nucleic acid, for example give the fragment of full length protein fragment coding.The appropriate polynucleotide of virtually any size can adopt, as long as it can provide clinical efficacy.
The polynucleotide that are used for the present composition and method can have any form, and these forms are conspicuous for those of skill in the art, comprise DNA, RNA, PNA, LNA, oligonucleotide, sub-thread or bifilar molecule etc.Nucleic acid can comprise any amount of known altered contents, and these altered contents can promote the stable of nucleic acid or strengthen the absorption of cell to them.These altered contents comprise those that USP6455292 etc. is discussed.
In a preferred embodiment, polynucleotide are as vaccine, for example dna vaccination.Synthetic and the using method of this dna vaccination will be discussed (for example, can referring to embodiment 5-8) in detail in other places of this description, and this vaccine can be an influenza hemagglutinin protein matter coding, can alleviate some symptom of influenza infection at least.This nucleic acid can be full length protein or its fragment coding, for example can cause immunoreactive antigenic peptides.
Nucleic acid can comprise coding or non-coding (for example regulating) sequence.Except being the peptide coding, nucleic acid also can be antiallergic molecule or ribozyme.For the discussion of the antigen molecule or the ribozyme of some known type, can be referring to USP 6455292 etc.
Suitable virion comprises the virion of partially or completely deactivation, can be used as the antigen of vaccine, as influenza, RSV and poliovirus etc.In a preferred embodiment, virus can be inactivating influenza virus.Typical influenza strain comprises A/PR/8/34 and Port Chalmers strain etc.In being also included within the subgroup vaccine of conventional method preparation.In another embodiment, also comprise the conventional filterable virus carrier that is fit to interanasal administration, include, but is not limited to adenovirus vector or AAV carrier, comprise one or more genes to the therapeutic protein coding.Any suitable therapeutic genes can adopt, and comprises the gene of suitable treatment gallbladder cystic fibrosis etc.
Suitable steroid comprises the traditional steroid that is used for the treatment of asthma, bronchospasm or other diseases, and these are known for a person skilled in the art.
Goal treatment reagent begins available any conventional liq and makes liquid formulation.Described liquid is preferably liquid, aqueous, and for example water (for example injection high-quality water) or any conventional buffer, described buffer can saliferous, also can not contain.PH to buffer will select, so that the therapeutic agent of stable protein or selected other types, and those skilled in the art grasp easily.Usually, this pH is within the physiological pH scope, although some protein is stable equally in wideer pH scope, for example under condition of acidic pH.Therefore, the pH scope of original liquid ingredients should be between about 1-10, and is more suitable between about 3-8, especially should be between about 5-7.As is known to the person skilled in the art, there are a large amount of suitable buffer can supply to adopt.Suitable buffer includes, but is not limited to sodium acetate, sodium citrate, sodium succinate, ammonium bicarbonate and ammonium carbonate.Usually, the concentration of buffer is about 1mM-2M, should be about 2mM-1M, and the more suitable 10mM-0.5M that is about especially should be about 50-200mM.If there is salt in the solution, then the concentration of salt generally is about 1mM-2M, should be about 2mM-1M, and the more suitable 10mM-0.5M that is about especially should be about 50-200mM.Suitable salt includes, but is not limited to NaCl.
Liquid formulation can have any form, as solution, suspension, serosity or colloid.
Liquid formulation can be chosen wantonly and comprise one or more conventional pharmaceutical excipients." excipient " refers generally to the chemical compound or the material that add for the effect that improves the API ingredients.Such example has anti-low temperature agent and anti-solvent, can guarantee or improve the stability of protein in spraying-lyophilization or spraying-freezing-constant pressure and dry process after the adding, and powder-product is in the future long-time stability and flowability.The normally mobile relatively freely solid particle of suitable protective agent; with can thickening or polymerization after water contacts; be inhaled in the patient body or enter in the patient body by other modes after harmless substantially, and can obviously effect not take place with therapeutic agent, thereby change its biological activity.Suitable excipient includes, but is not limited to protein, as human albumin, bovine serum albumin, gel, immunoglobulin; Carbohydrate is as monosaccharide (galactose, D-manna are lain, sorbose etc.), disaccharide (lactose, trehalose, sucrose etc.), cyclodextrin and polysaccharide (Raffinose, maltodextrin, dextran etc.); Aminoacid, as monosodium glutamate, glycine, alanine, arginine, histidine, and hydrophobic amino acid (tryptophan, tyrosine, leucine, phenylalanine etc.); Methylamine is as betanin; Excipient salt is as magnesium sulfate; Polyhydric alcohol is as trihydroxy or more polyhydroxy sugar alcohol, for example glycerol, Chi Sue alcohol, arabitol, xylitol, sorbitol and mannitol; Glycerol; Polyethylene Glycol; Polypropylene glycol and oxirane addition polymers; Surfactant; Their combination.Preferred excipient comprises trehalose, sucrose and mannitol.Another kind of excipient mucoadhesive is commonly used to strengthen contacting of API and mucomembranous surface.The example of mucoadhesive comprises chitosan, dermatan sulfate, chrondroitin and pectin.In addition, in the liquid formulation that adapts to SFD process described here, can add conventional cosolvent, in order to improve the dissolubility of API.
If the use mucoadhesive, their consumption generally is about 1-95wt%, should be about 1-50wt%, and the more suitable 5-50wt% that is about especially should be about 5-20wt%.The concentration of anti-low temperature agent is generally between about 5-95wt%.
In one embodiment, dried powder of the present invention will combine with extender or carrier subsequently, reduces the concentration of therapeutic agent in the intravital powder of input patient; That is to say that the bolus volume of unit dose is suitable big.Also usable extenders improves the dispersibility of powder in dispersal device, and/or improve the transport property of powder.This is different with use extender or carrier in spraying-dry run.Suitable extender generally is crystalline solid (to avoid suction), includes, but is not limited to lactose and mannitol.Correspondingly, if add extender such as lactose, its additional proportion can change, and the therapeutic destination agent should be about 99 with the ratio of extender: 1-1: 99, more suitablely be about 1: 5-5: and 1, especially should be about 1: 10-1: 20.
Liquid formulation of the present invention can atomize with any conventional method.For example, liquid can pass through double flowing nozzle, high pressure nozzle or rotating disk spraying, perhaps utilizes the atomizing of soniclizer or vibratory orifice plate aerosol generator (VOAG).In one embodiment, liquid formulation is by high pressure nozzle, as BD AccuSpray nozzle atomization.
In a preferred embodiment, can optimize atomization condition, make the average quality diameter of atomised droplets be at least about 20 μ m, should be between about 35-300 μ m, more suitable between about 50-300 μ m, especially should be between about 50-100 μ m.Available conventional method is optimized droplet size.Contingent condition has atomization air flow, atomization air pressure, flow rate of liquid etc.Can also change the type and the size of nozzle.Be easy to measure the drop size with conventional method, as use laser diffractometry.The size of dried particles can be measured with routine techniques, as scanning electron microscope (SEM) or laser diffraction.For example, Fig. 4 and 18 is respectively the typical particle diameter distribution with the fluid sample of laser diffractometry mensuration and dry powder sample, and sample prepares with embodiment 1 described method.
In one embodiment, freezing atomizing particle is near dry under the normal pressure, and as discussed in other places of this description, the size of atomised droplets was at least about 20 μ m, should be between about 20-300 μ m, and more suitable between about 35-100 μ m or 50-100 μ m.
After the liquid formulation atomizing, drop is frozen into solid particle rapidly.After atomization steps, drop should be freezing immediately, and is perhaps almost freezing immediately.
In one embodiment, during freezing drop, drop is immersed in the cold liquid, its temperature is lower than the solidification temperature of the liquid formulation that forms atomized drop.In a preferred embodiment, the temperature of cold liquid is about-200 ℃ to-80 ℃, should be about-200 ℃ to-100 ℃, preferably is about-200 ℃ (liquid nitrogen temperature is about-196 ℃).Any suitable cold liquid can adopt, and comprises liquid nitrogen, liquid argon and hydrogen fluorine ether, or compressed liquid, as compressed liquid CO
2, helium, propane or ethane, or similar inert fluid, as known in the art.For example, in one embodiment, liquid therapeutic ingredients atomizes by spray nozzle, and this spray nozzle is positioned at the container top that holds suitable cold liquid such as liquid nitrogen.Drop with solidify immediately after cold liquid contacts.Embodiment 2 is exactly the inactivating influenza virus particulate composition with this freezing method preparation.
In another embodiment, drop solidifies in the process by the gas in the cooling chamber (for example cold air, nitrogen, helium or argon), and gas temperature is lower than the freezing point of drop.In a preferred embodiment, cold air temperature is about-5 ℃ to-60 ℃, and more suitable being about-20 ℃ is to-40 ℃.Available conventional method refrigerating gas, as utilize cooling coil, heat exchanger or cooler.Gas temperature can reduce with conventional method, for example produces the temperature that is lower than freezing point with liquid nitrogen, dry ice or similar low temperature agent.Embodiment 1a and 1b have introduced instrument and the method that is used to prepare the present composition, wherein atomized drop in by the process of suitable cooling chamber by gas cooled.
Behind the solid particle that formation is solidified, dried particles forms powder." drying " refers to that content liquid can ignore, and for example particulate water capacity makes it be easy to disperse to form aerosol, for example in suction apparatus.This water capacity is usually less than about 15wt% water, should be lower than 10%, more suitablely is lower than about 1-5%.
In one embodiment of the invention, solidify drop by dry freeze method (lyophilization under the vacuum) drying, employing be conventional dry freeze instrument.The method generally is called " spraying-freeze-dried " or SFD method, and the compositions for preparing with the method is called " spraying-freeze-dried " or SFD compositions.For example, in one embodiment, when granule spray into solidify in the container (for example Virtis freeze-dried bottle) that fills liquid nitrogen after, container can be connected in the conventional dry freeze instrument, then unnecessary liquid nitrogen vaporization is fallen.The aerosol that solidifies is dry within about 48 hours usually, and water capacity is less than about 1wt%.Perhaps, drop is being solidified near in the non-pressurized cold air, and choose wantonly, put into the dry freeze bottle then and carry out dry freeze in condition lower part drying near normal pressure (as described below).
In another embodiment, the drop that solidifies is passing through sublimation drying near in the non-pressurized dry cold airflow (for example air, nitrogen or helium).Here used " near normal pressure " refers to the atmospheric pressure of about 0.5-5.Gas temperature can reduce by any conventional method, for example uses liquid nitrogen, dry ice or similar low temperature reagent.Exsiccant like this granule of the present invention is called " spraying-freezing-normal pressure-drying " granule sometimes.In a preferred implementation, atomized drop is freezing and dry in same " spraying-freezing-normal pressure-drying " chamber, makes freezingly and dry to finish in the same step.
A set of equipment of drying solid frozen particle and the USP4608764 that method is seen Leuenberger in approaching non-pressurized cold air.Be also shown in embodiments of the invention 1a and 1b.The conventional equipment of other types also can use.
In a preferred implementation, as described in embodiment 1b and 11, freezing atomizing particle is near in the non-pressurized cold air, and is dry under the condition that can promote the granule atomizing.In most preferred embodiment, freezing atomizing particle is in dry run, and is dry under the situation that vibration component, internals, mechanical agitation member or this several situation combinations exist.Here used term " internals " refers to any physical barriers object in chamber (for example SFD chamber) or the fluid bed, and for example catch, baffle plate or other stop object.This processing can make granule reach fluidized state.The method and apparatus that reaches this fluidized state is discussed in embodiment 1b and 11.
Embodiment 1b and 11 described method and apparatus can also prevent channel.Channel is one of worst fluidization characteristics of fine granular, can occur under low fluidizing velocity or high fluidizing velocity.When gas made progress by the space between distributor and the bed surface, channel just took place.These vertical channels laterally move past fluid bed in time, and the fluidization of bed is stopped.Also have gap on the bed, infiltrate in these vertical channels.Along with the increase of air velocity, the granule for some extreme viscosity not only forms little channel, and forms big channel, also claims rat hole.Why producing this problem, is because intergranular active force is obviously more much bigger than the power that fluid is applied on the granule.
Be difficult to fluidisation with spraying-refrigerated powder such as double flowing nozzle, high pressure nozzle or ultrasonic nozzle.When dry, these granules are easy to form channel or reunite, and make their be difficult to finish-drying not even rapidly on fluid bed.The present inventor recognizes, in dry run, introduce vibration component, internals, mechanical agitation member or integrated use they, can make these granule generation fluidisations effectively.
In another embodiment, freezing droplet can distil and the dry freeze combined drying in exsiccant cold air (for example air) by above-mentioned near under the normal pressure.For example, can will transfer in the dry freeze device further dry near the exsiccant compositions in normal pressure lower part (for example forming cake or the powder that still comprises excess liq).
Available conventional method is collected dry compositions.In one embodiment, dried particles can be collected by filter, moves then and does medical application.Understand the equipment that this method and this method adopts, can be referring to embodiment 1a and 1b and Figure 1A and Figure 1B.In another embodiment, spraying-freezing-normal pressure-dried particles is collected in the product container.The part dried particles can form loose cake, and further distillation can be removed wherein residual moisture in dry cold air stream, also they can be transferred in dry freeze device or other the suitable devices, further decompression (being lower than normal pressure) drying.
Basic identical with the character (for example particle diameter, permeability etc.) that above-mentioned any method dried granules is had.
Gas atomization of the present invention-freeze-dried process has particularly utilized the process of vibration component and/or internals, and a kind of economically viable method that can produce dried particles and can increase productive rate is provided.Have by the compositions of described method preparation and to be convenient to by character such as respiratory system administrations.Spraying-freeze-dried method of being introduced with the United States Patent (USP) 6284282 of Maa is different, and embodiments of the present invention only just can produce dried particles with a set of equipment.Atomizing among the present invention, freezing and dry should finishing at same container do not need to shift sample, thus can contaminated samples, can not reduce productive rate yet.Whole operation also can be finished continuously, thereby has improved efficient." continued operation " refers to not exist intermittently between each step, and/or do not relate to physical separation (for example not needing the transfer of granules of freezing atomizing dry in another container).Other sprayings-freeze-dried technology of pharmaceutical compositions often comprises another dry freeze step, and it need be transferred to frozen particle in the dry freeze device from spraying-refrigerating chamber.This additional step has reduced the commercial viability of spraying-freeze-dried technology, and because the moisture that is wrapped in the granule is partially thawed, granule is reunited easily.
After drying was finished, the present composition can form free-pouring powder.Size (geometric diameter) and shape before the dry porous particle of described compositions and the freezing droplet drying are roughly the same.
Dried particles of the present invention has required aerodynamic property.The inertial collision of dried particles and gravity descent property have determined their deposit properties in the animal breath road.The conventional method of available this area is measured this deposit properties.For example, aerodynamic diameter is defined as the subduplicate product (d of actual particle diameter and the ratio of grain density and water density
Ae=(sg)
1/2d
p, sg=ρ
Granule/ ρ
Water, d wherein
AeBe the granule aerodynamic diameter, d
pBe particle diameter).
Dried powder of the present invention also has other required character.Embodiment 9 and 10 has introduced the ρ for example with the present invention
GranuleSome character of the analgesic composition of method preparation.Described granule has required form (shown in SEM) and density.In addition, described granule residual powder wherein after using conveyer device is few, demonstrates than better stability such as liquid insulin ingredients, and forms again in liquid easily.
The present composition can be used to treat various diseases, comprising diabetes, infectious disease or available any disease that description is treated at the therapeutic agent or the other treatment reagent of other local discussion.In a preferred implementation, the present composition is a vaccine.
One aspect of the present invention provides a kind of method that the patient of needs treatments is implemented to treat, comprise to described patient use effective dose, with the pharmaceutical composition of the inventive method preparation." effective dose " refers to cause the amount of required reaction here.For example, the immune composition of effective dose is meant that this dosage can effectively cause and can surveys immunoreation.Effective dose can be determined according to conventional methods by rule of thumb, consider various common factors, and as patient age, body weight and/or clinical condition, medication and time dosage are arranged, or the like.The patient can be any animal, is preferably mammal, for example farm-animals or domestic animal, and perhaps mouse, hamster, Cavia porcellus, rabbit etc. more are preferably the people.
The present composition can be used with any approach known to the those skilled in the art, includes, but is not limited to respiratory system, intranasal, internal rectum, intravaginal, Sublingual, oral cavity or parenteral route.In one embodiment, described compositions is applied in the mucosal tissue, includes, but is not limited to the mucosal tissue of nasal passage and nasal sinuses.In a preferred implementation, the present composition is granted the patient by respiratory system." by the respiratory system administration " refers to that here medicament enters pulmonary in some cases subsequently by nasal cavity and nasal sinuses by nose (intranasal) administration.
Can adopt conventional medication.Suitable administration apparatus (for example inhaler) is known in this area.Typical explosive-feeding processing device includes, but is not limited to the device that USP 09/879517 (being registered in 6/12/01) and 09/758776 (being registered in 1/12/01) are introduced.Dosage can be determined according to conventional method well known by persons skilled in the art.For example, compile " pharmacological basis of treatment ", Macmillan Publishing Co., New York referring to Goodman and Gilman.The factor of considering comprises the activity of concrete institute with medicament, the metabolic stability of medicament and the order of severity of action time, mode of administration and time, drug regimen, discharge rate, the species of receiving treatment, patient's age, body weight, general health situation, sex, diet situation and specified disease.The dosage (for example effective vaccinated dosage) that causes effective immune response is familiar with to those skilled in the art.
It is a kind of to the method for patient's administering therapeutic compositions with treatment health disorders (for example uncomfortable or disease) that the present invention provides on the other hand, comprises patient's nasal passage and/or nasal sinuses passage mucosal administration pharmaceutical composition of the present invention.Another embodiment is to patient's administering therapeutic method for compositions, comprises patient's nasal passage and/or nasal sinuses passage mucosal administration pharmaceutical composition of the present invention.Another embodiment relates to the unit dose of administrator or Diskus, comprises the effective dose of pharmaceutical composition of the present invention.
With the dried agent of other liquid formulation or other types, to compare as spraying-dry ingredients, the present composition utilizes intranasal administration, can obtain better therapeutic.Referring to embodiment 2 and 3.Therefore, when the present invention relates to that the patient implemented intranasal administration, reduce the amount that produces the required therapeutic agent of curative effect, it comprises the pharmaceutical composition of the present invention by the intranasal administration effective dose to described patient.
On the one hand, the present invention relates to excite the immunoreactive method of patient, comprise the immune composition of the present invention of using effective dose to the patient.Here used term " immunoreation " comprises various mechanism, for example when antigenic substance is invaded in the cell of many cells tissue or the extracellular liquid, and just the create antagonism antibody of antigenic substance of cell tissue.The antibody of Chan Shenging can be any in all kinds of immune antibodys like this, as immunoglobulin A, D, E, G or M.Also comprise the reaction of other types, for example cell and humoral immunity.Antigenic immunoreation has been obtained further investigation, and wide coverage has been arranged.Immunologic summary is seen that Roitt I. shows (1994) " amynologic basis " (Essential Immunology), Blackwell ScientificPublications, London.Immunization method is that conventional method is (for example, referring to volumes " the existing test report of immunology " such as John E.Coligan, John Wiley﹠amp; Sons., Inc.).
On the one hand, the present invention relates to vaccine (being used for stimulating the immune reagent of biological tissue) for the injury that may occur in the future provides protection.For example, influenza vaccines can prevent the infection of influenza virus at least on limited extent.That is to say that vaccine can be alleviated some symptom that influenza infection causes at least.Vaccine combination of the present invention can have protein (as subgroup vaccine), virion or be the form of target antigen coded DNA.
Most of infectious agents produce the Pathophysiology effect by mucosa after entering in the body.In the inlet primary importance, the mucosa IgA that produces by the part can provide protection at infectious disease to the inhibition of infectious agents.Though traditional immunization route (as IM, ID etc.) is easy to the initiating system immunoreation, mucosa reaction generally is difficult to realize.The advantage of intranasal (IN) delivery of dry powder vaccine is that it is initiating system and mucosal immunoreaction simultaneously.In addition, the conveying of IN powder vaccine can reduce required dosage, because the suction of mucosa powder medicine is effective.
Embodiment 4 is to the influenza Study on Stability.The dry freeze method can not cause negative effect to particulate stability, but particulate grinding then makes granule stability sharply descend to freeze-dried.
Embodiment 5-7 has introduced preparation and the using method of DNA influenza vaccines.The inventive method can be used for preparing and/or carrying the vaccine combination that comprises dna molecular.Produce dna vaccination, for example the method for influenza vaccines is known in this area, discusses in other places as this description.Embodiment 5 has introduced a model system, in this model, will be marker gene coded DNA plasmid by the intranasal mode, the luciferase of Lampyridea is introduced in the mouse body, this plasmid can be a liquid formulation, also can be dried (FD) ingredients prepared according to the methods of the invention.Being expressed in the nose tissue of luciferase gene is observed, rather than in the lung tissue.IN poudrage gained gene expression dose can be compared with liquid formulation.Embodiment 6 and 7 has introduced how to prepare the dna vaccination that comprises influenza hemagglutinin (HA) coded sequence, and with the remarkable reaction of this vaccination to mouse back initiation on one's body.The SFD ingredients that contains the excipient trehalose prepared according to the methods of the invention is by behind the intranasal administration, and the antibody response of initiation compares by the liquid formulation of the similar dosage of intranasal administration or much better than by the ingredients of muscle administration.
Embodiment 8 has introduced a kind of immunization protocol, and wherein basic vaccination is undertaken by the dna encoding influenza hemagglutinin, produces a large amount of influenza virus particles subsequently.This scheme can produce extra high antibody response.
On the other hand, the present invention relates to be used for the pharmaceutical composition of respiratory system administration, it comprises insulin; Also relate to the method for preparing compositions and treat the patient with said composition.Carry insulin to have several advantages by respiratory system, for example compare with administering modes such as Intradermal or subcutaneous injections, it can increase patient's adaptability, and diabetics needn't be injected continually voluntarily.Embodiment 9 and 10 has provided some character of insulin ingredients of the present invention.
Among the embodiment 2-10 that here provides, compositions is called " SFD " sometimes by the preparation of spraying-freeze-dried (dry freeze) method.In the compositions of these embodiment, particulate average diameter is at least about 20 μ m.These compositionss can be compared (embodiment 1,11 and 12) with spraying-freezing-normal pressure-drying means, and therefore above-mentioned discovery is equally applicable to the compositions with a kind of method preparation in back.Pro-is addressed in the following examples, and all temperature are all degree centigrade to be unit, and are not calibrated; Except as otherwise noted, all part and percents all refer to weight portion and percetage by weight.
Embodiment
1a) the method and apparatus of preparation the present invention spraying-freezing-normal pressure-dry pharmaceutical compositions
Many equipment all can be used to make pharmaceutical composition of the present invention.Fig. 1 has shown the overall schematic 10 that can be used for spraying of the present invention-freezing-normal pressure-drying equipment.Be to be used to prepare active medical components (API) below, for example be fit to method example with the API of respiratory system administration.Liquid feeding line 12 realizes that with atomizer 14 fluid is connected.The mixture of API and a kind of suitable liquid of packing in the liquid feeding line will further be explained below.Nozzle 14 is arranged on spraying-freezing-normal pressure-hothouse 16 inside.In a preferred implementation, atomizing line 18 (for example adopting Compressed Gas) carries out the interface with nozzle 14 and contacts, so that aerosolized mixture.Atomization gas can comprise nitrogen, oxygen or air.The nozzle of other general types also can effectively produce suitable atomizing particle size, comprises double-current nebulizer, high-pressure atomizer, ultrasound atomizer, is more preferably vibration implication colloidal sol generator (VOAG), known they each can both produce more uniform particle size distribution.Cold liquid (for example nitrogen) or solid (for example dry ice) can be placed in the hothouse, help the atomized drop rapid solidification.
Between cooling system 20 and hothouse 16, the temperature maintenance that is used for making the cold air that enters hothouse 16 is within required scope in cold air input line 24 for temperature controller 30.Additional gas filter 32 between chamber 16 and cooling system 20, is used for collecting the residuals of escaping from from chamber 16 in cold air return wire 26, thereby avoids polluting cooling system 20.Valve 34 lays respectively between temperature controller 30 and the additional filter 32 in cold air input line and cold air output lead 24,26, so as safeguard or other operation sequences in hermetically drying chamber 16.
A pump or aerator 36 are installed between additional gas filter 32 and the cooling system 20 in air output lead 26, cold air is circulated between cooling system 20 and hothouse 16.Air inlet and air outlet valve 38 are positioned at the import 40 and outlet 42 places of each cooling chamber 22, each cooling chamber are separated separately, so that safeguard or other operation sequences with circulating cold air line 24,26.In addition, bypass valve 44 is arranged in bypass valve line 46, and this line makes and forms fluid between cold air input line 24 and the cold air output lead 26 and connect, so that hothouse 16 is when disconnecting with cooling system 20, the cold air in the cooling system 20 still can circulate.
Because nozzle 14 is arranged in hothouse 16, the operating temperature of nozzle 14 is lower than the freezing point of the mixture that enters nozzle 14, and therefore, spray valve 14 is freezing easily, hinders mixture to atomize with suitable manner in hothouse 16.Therefore, on valve 14, connected heating tape 48, made the valve temperature be kept above the freezing point of mixture.Other conventional methods that make the temperature of nozzle 14 be kept above the mixture freezing point also can adopt, as known to those skilled in the art.
In operating process, atomizing API passes through nozzle inlet chamber 16, and is solidified by the cold air from cooling system 20 inlet chambers 16 rapidly.Circulation gas should make granule remain on the fluidisation attitude in chamber 16.Remain on the fluidisation attitude and be collected in the process in the filter 28 at granule, the circulation cold gas can be removed and is wrapped in the liquid in the refrigerated solid particle in chamber 16, thereby makes particle drying.The lasting circulation of cold air can make the humidity in every granule be reduced to insignificant degree.After elementary drying is finished, can choose wantonly circulating air progressively is heated to room temperature, so that in the process of taking out sample, carry out secondary drying and reduce also tide.
Perhaps, can choose wantonly and take out the lyophilization granule from filter 28, and send in dry freeze device or other appropriate device, these devices are worked under reduced pressure, and residual moisture can be removed at this, and granule obtains finish-drying.Also in freezing state, the dry freeze device just begins to remove the moisture in the granule to granule, and moisture directly becomes gas phase from solid phase, as known in the art.
In spraying-freezing-normal pressure-dry run, introduce spray step and can solution be processed into dry particulate matter near under the condition of normal pressure.Can formed aerocolloidal API easily near processing spray chilling material under the normal pressure, these API are fit to the dispensing patient to be used.In addition, the method for introduction of the present invention is for providing economic approach at commercial production proper A PI.
1b) use the vibrated fluidized bed of being with internals to prepare the method and apparatus of the present invention's spraying-freezing-normal pressure-dry pharmaceutical compositions
A version of Figure 1A apparatus shown is seen Figure 1B.This variant comprises vibration tool (49) and special internals (50).Vibration component and internals can make the frozen solid granule reach the fluidisation attitude, because they are passing through sublimation drying near in the non-pressurized dry cold airflow.When frozen particle was relatively more sticking, the method was particularly useful.When fluidisation and the freezing powder of elutriation viscosity, this method is very valuable in the process that forms muffin.
In order to improve productive rate, can design a system of sealing fully, prevent freezing powder escape.The powder that available filter disc or papery filter disc or filter paper capture are come out from following fluid bed elutriation.When fluidisation and the freezing powder of elutriation viscosity, vibration component, internals, mechanical agitation member or their combination are very useful.In sublimation process, the frozen particle permeability increases (having lightened), and the aerodynamic behavior changes.The part dried granules can go out the loose filter cake of interruption-forming at filter disc, can utilize dry cold airflow that residual moisture is therefrom being removed near distillation under the normal pressure.
Be similar to the method among the embodiment 1a, send into hothouse 16 by the nozzle API that will atomize, by the cold air that enters hothouse 16 from cooling system 24 freezing rapidly (seeing Fig. 1 b).In operating process, vibrator 49 is transferred to optimum frequency (0-100Hz) and amplitude.Make frozen particle generation fluidisation from the dry cold flow activating QI that cools off line 24 and enter from hothouse 16 bottom surfaces.The bulky grain agglomerate is broken under the help of the special internal member (still) 50 that vibrates and be positioned at chamber 16.Under this operating condition, the channel that cohesive powders will occur usually can reduce or thoroughly eliminate.As a rule, the easy elutriation of little frozen particle, and send into filter 28 by fluidized gas.Muffin on the filter 28 is assembled in fluidisation and elutriation process gradually.
Owing to used above-mentioned granule sealed system, can obtain high flow rate, suggestion is adopted high flow rate in the process that forms muffin, to increase rate of drying.In dry run, also adopt high flow rate, because freezing powder is faster under than slow fluid bed state in the dry rate under the high flow rate fluid bed state.The gas atomization of band vibration component of the present invention and/or internals-freeze-dried process provides economically viable method for production dried particles, increase productive rate.
In addition, higher if desired dry rate can be used in this dry run at a high speed or recirculating fluidized bed.High speed or recirculating fluidized bed generally are made up of the close fluid bed of bottom and the rare fluid bed and the powder send-back system at top.In this process, frozen particle is by cold flow activating QI fluidisation and transport, and is collected by the cyclone separator at top, turns back to close fluid bed by custom-designed powder valve then.For ease of cooling, should use inner cyclone separator, custom-designed returns valve with certain resistance only allows powder to get off, rather than the by-pass activating QI.For the crushed particles agglomerate, increase the granule circulation, also should use similar internals.
Perhaps, choose wantonly and take out the lyophilization granule from filter, and send into dry freeze device or other appropriate device, residual moisture is removed in described dry freeze device or the operation under reduced pressure of other devices, makes the granule finish-drying.Also when freezing state, lyophil apparatus has just been sloughed the moisture in the granule to granule, because moisture is from the solid-state gaseous state that directly become, as known in the art.
The gas atomization of band vibration component of the present invention and/or internals-freeze-dried method provides economically viable method for production dried particles, increase productive rate.
The particulate intranasal administration of embodiment 2 inactivating influenza virus
The particulate dry powder ingredients of the full inactivating influenza virus A/PR/9/34H1N1 of preparation in spraying-lyophilization batch operation.The influenza virus ingredients is sneaked in the aqueous solution, use BD AccuSpray nozzle atomization then.The liquid particles sized data is measured in the about 2 inches place of distance nozzle tip with the Sympatch diffractometer and is obtained.The particle diameter intermediate value that produces under these concentration is about 50 microns.See Fig. 4 with the typical particle diameter distribution that BD AccuSpray nozzle produces.Liquid nitrogen is put into Virtis freeze-dried bottle, bottle is placed on below the nozzle.About 3 inches of distance between nozzle and the liquid nitrogen.Atomized drop is with freezing immediately after liquid nitrogen contacts.Bottle is connected on the dry freeze device, and unnecessary liquid nitrogen is evaporated rapidly.Refrigerated aerosol is generally dry within 48 hours, and water content is lower than about 1wt%.
In an experiment, measure the immunoreation intensity of the various influenza vaccines ingredients generations of carrying by intranasal (IN) or muscle (IM).This research is object of study with the Mus, has measured following several groups:
Group 1-IN.100 μ g influenza * Ag is in 50 μ l liquid
Group 2-IM injection.100 μ g influenza * Ag are in 50 μ l liquid
Group 3-IN administration.100 μ g influenza * Ag in the 10mg trehalose, the lyophilization powder
Group 4-IN administration.100 μ g influenza * Ag in 10mg trehalose+chitosan, the lyophilization powder
Group 5-IN administration.100 μ g influenza * Ag in 10mg trehalose+chitosan, spraying-freeze-dried (SFD) powder
Group 6-IN administration.Has only the cryodesiccated trehalose of 100mg
* the full influenza virus A/PR/8/34H1N1 of deactivation
Mus is respectively at the 0th week, the 3rd week and 3 vaccines of the 6th week inoculation.Collect blood serum sample in the 3rd week, the 5th week and the 8th week, collect nasal wash in the 8th week.
Behind each inoculation influenza vaccines, blood sampling is measured the immunoreation amplitude to influenza vaccines, the concrete antibody response of measuring vaccine (Ab).After each inoculation, also measure the amount of powder of sending into.Measure such as factors such as immunoreation power and powder conveying capacities with conventional method.Figure 2 shows that each postvaccinal serum Ab titre.Generally speaking, though the serum Ab accumulation titre of sending into by IM is higher than the titre of sending into by intranasal, even the spray chilling that IN sends into-dry influenza vaccines dosage lower (being low to moderate 0-10% when inoculating for the second time) also can reach quite high serum Ab reaction.Generally speaking, this experiment shows that under the sufficient situation of vaccine dose, the serum Ab reaction level that the atomizing freeze drying influenza vaccines of IN input can cause is suitable with the IM group, and than IN liquid group height.
As shown in table 1, all IN influenza vaccines groups can both cause positive nose IgA reaction, and IM injection and IN negative control group obtain negative nose IgA titre.This studies show that IN input SFD influenza vaccines can cause nasal mucosa reaction and systemic immunity reaction simultaneously.
Table 1 nose IgA titre
| Group 1 (IN, liquid) | Organize 2 IM | Organize 3 IN, powder | Organize 4 IN, chitosan | Organize 6 SFD, chitosan | Organize 7 IN, trehalose |
| ????80 | ??＜20 | ????＜20 | ????20 | ????40 | ????＜20 |
| ????160 | ??＜20 | ????80 | ????20 | ????40 | ????＜20 |
| ????160 | ??＜20 | ????＜20 | ????40 | ????40 | ????＜20 |
| ????160 | ??＜20 | ????20 | ????40 |
This embodiment has compared containing and the not immunoreation of the SFD influenza all-virus of chitosan-containing to brown Norway Mus IN input various dose.Respectively organize sample below having measured, every group contains 4 Mus:
1-IN。1 μ g influenza * Ag, in the 5mg trehalose, SFD
2-IN。1 μ g influenza * Ag, in 5mg trehalose+chitosan, SFD
3-IN。10 μ g influenza * Ag, in the 5mg trehalose, SFD
4-IN。10 μ g influenza * Ag, in 5mg trehalose+chitosan, SFD
Present embodiment adopts the full influenza virus strains A/PR/8/34H1N1 of deactivation.Every Mus IN inoculates 3 times.The result shows that the influenza vaccines of the comparable 1 μ g of the influenza vaccines of 10 μ g dosage cause stronger serum I g and nose IgA reaction, and the ingredients of the comparable not chitosan-containing of the ingredients of chitosan-containing causes stronger serum Ab reaction.
Embodiment 4 influenza activity researchs
A series of experiments and process of lapping can influence the influenza immunocompetence.Under study for action, use hemagglutinin result of laboratory test (HA) as the active index of influenza.This chemical examination detects the HA titre of influenza vaccines, and the ability that it condenses the chicken erythrocyte based on influenza virus, this ability are to weigh the index of influenza vaccines effect.In brief, two inactivating influenza virus particulate samples of preparation; First sample dry freeze, second sample elder generation dry freeze grinds then.This sample grinds with Wig-L-Bug microsphere grinding machine.This grinder adopts one inch rustless steel bottle with cover.Sample is put into bottle, the single stainless steel ball of load, cover lid is fixed on the grinder then.This bottle vibrates from the beginning to the end with certain speed, and this speed at the appointed time can change in the section.After the grinding, take out sample with little scraper.Influenza powder freezing and that grind recovers original liquid influenza vaccines concentration (based on total protein concentration) again.Influenza virus activity after the recovery can be determined by the HA titre and the initial flow influenza vaccine that compare them.The gained result is as follows:
Initial liquid influenza vaccines HA titre＞6,000 ten thousand
Dry freeze influenza vaccines HA titre＞6,000 ten thousand
Dry freeze abrasive flow influenza vaccine HA titre=4352
Initial liquid influenza vaccines HA titre＞6,000 ten thousand
Spraying-freeze-dried influenza vaccines HA titre＞6,000 ten thousand
These data show that with regard to the HA titre, the dry freeze process does not have much affect to vaccine activity.But process of lapping sharply descends the HA titre.Determined the activity whether the SFD method influences influenza vaccines with identical HA titre.Influenza vaccines powder with the preparation of SFD method returns to initial liquid influenza vaccines concentration (in total protein concentration).Reconstruct influenza vaccines activity is determined by the HA titre of they and primary flow influenza vaccine relatively.
The result shows that the SFD method does not cause harmful effect to the influenza vaccines activity, and administration is convenient in the influenza vaccines powder energy free-flow of preparation, can keep vaccine activity fully simultaneously, does not need to increase in addition grinding operation.
The IN input of the plain enzyme of embodiment 5 plasmid DNA (" naked DNA ") coding fluorescence
Efficient gene is treated and need be from the protein expression of input gene based on the immunity of DNA.For this reason, reporter gene system commonly used is as the archetype of determining that this therapy is whether feasible.The activity of importing luciferase after various DNA dosage and the ingredients by IN has been measured in this research.
A. liquid formulation
In used plasmid, the luciferase coded sequence of Lampyridea is subjected to the control of CMV promoter (pCMV-LUC).PCMV-LUC obtains from the Aldevron LLC that is positioned at North Dakota State Fa Geshi the 15th street No. 3233 (postcodes 58104).The preparation liquid formulation, the dosage of preparation 50 μ g or 100 μ g in 50 μ l PBS is input to the ingredients of these two kinds of dosage in the brown Norway Mus body by IN.DNA is after 24 hours in input, collects nose tissue and lung tissue, and homogenize is with the activity of fluorescence assays method mensuration luciferase.
Figure 5 shows that the uciferase activity of in the nose tissue, measuring, rather than in lung tissue, measure.It is higher than the uciferase activity that 50 μ g DNA obtain that IN imports 100 μ g DNA.
B. the comparison of liquid and dry powder ingredients
Prepare the pCMV-LUC liquid formulation as mentioned above.According to embodiment 4 described dry freeze and Ginding process, prepare dry powder (FD) as excipient with trehalose.Also there is the chitosan excipient in some ingredients.The liquid formulation of preparation 100 μ g dosage in 50 μ l PBS, preparation 100 μ g dosage of powder ingredients in the total powder weight of 5mg are imported their in mouse body, as mentioned above analyzing samples.
Fig. 6 shows that dry powder and liquid formulation can both obtain high uciferase activity in the nose tissue, and lung tissue can not.IN input dry powder can obtain the uciferase activity suitable with liquid formulation.This result demonstrates the probability with SFD powder type input DNA.
Embodiment 6 DNA influenza vaccines
Prepared plasmid with conventional recombinant technique, wherein be subjected to the CMVPro sequence control (Robinson etc. (1995) of CMV early promoter for influenza virus surface antigen hemagglutinin coded DNA sequence, Vaccine 95, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp.69-75).With routine techniques plasmid purification (pFLU-HA), be inoculated in the mouse body: muscle (IM), intranasal, liquid formulation (IN-liquid) and intranasal SFD, contain trehalose excipient (IN-SFD-trehalose) with several method.Measure serum Ab reaction.As shown in Figure 3, the serum Ab reaction that the SFD influenza vaccines of IN input cause is suitable with the IM injection at least, and is higher than the reaction that the input of IN liquid causes.In this research, IN SFD influenza vaccines demonstrate the characteristics that are better than conventional IM injection by kind.
Embodiment 7 usefulness DNA influenza vaccines carry out immunity
Initial results based on IN DNA powder input as implied above is the immunoreation of more various dna vaccination ingredients, has carried out more massive research.The liquid formulation (in PBS) or the dry powder ingredients that have prepared the pFLU-HA plasmid, the wherein optional trehalose/chitosan that comprises.Two types dried ingredients: FD (standard freeze-dried ingredients) and SFD (spraying-freeze-dried (dry freeze) ingredients) have been used.The every kind of dried ingredients that contains 50 μ g plasmid DNA is by intranasal (IN) administration, and quite the liquid formulation of dosage is by in muscle (IM) or the IN input brown Norway Mus body, and the time was respectively the 0th day, the 21st day and the 42nd day.Get serum sample at the 21st, 35 and 56 day, got nasal wash at the 56th day.
Fig. 7 shows that the powder gained serum antibody titer of IN input is suitable with the IM injection, and stronger than the liquid formulation of IN input.At immune commitment, the Ab reaction that IN SFD/ chitosan ingredients causes is the strongest.This shows, uses SFD/ chitosan ingredients and can reduce dosage of inoculation and/or administration frequency.
Table 2 shows that the minority animal in several groups of samples that carry out IN SFD DNA input, all experimental grouies all lack nose IgA reaction.
Table 2 nose IgA titre
| ??IM | IN liquid | ??FD | The FD/ chitosan | ????SFD | The SFD/ chitosan | |
| Mus 1 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????＜10 | ????＜10 |
| Mus 2 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????＜10 | ????＜10 |
| Mus 3 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????＜10 | ????＜10 |
| Mus 4 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????＜10 | ????＜10 |
| Mus 5 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????10 | ????10 |
| Mus 6 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????＜10 | ????10 |
| Mus 7 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????＜10 | ????＜10 |
| Mus 8 | ??＜10 | ????＜10 | ??＜10 | ????＜10 | ????＜10 | ????＜10 |
| Mus 9 | ??＜10 | ????＜10 | ????＜10 | ????＜10 |
The total result of this research demonstrates SFD/ chitosan DAN ingredients and cause potential advantage in better serum and the nasal mucosa immunoreation in animal model.
Embodiment 8 influenza dna fundamental immunities+viral booster immunization scheme
Be a lot of diseases recently, the immunization method that comprises HIV exploitation is so-called " basis-reinforcement " method, wherein primary " basis " immune and secondary " booster immunization " adopt different types of vaccine (Immunology Today, Apr 21 (4), 163-165,2000).For example, kind of a plasmid dna vaccination be can lead, subgroup protein inactivation of viruses or carrier DNA preparation reseeded then.This research is adopted this method to probe into by different immunization routes and combination approach and is imported immunoreation usefulness after the various ingredients.
The preparation in liquid or dried ingredients (contain/do not contain the FD of trehalose/chitosan and contain/do not contain the SFD of trehalose/chitosan) of pFLU-HA plasmid is as described in embodiment 5.These ingredients are used for No. 1 and No. 2 immunity (fundamental immunity).
For carrying out No. 3 immunity (booster immunization), preparation inactivated influenza vaccine in PBS (liquid formulation) or trehalose/chitosan (dry powder ingredients).Every component becomes 2 subgroups: a winding is subjected to IM flow of liquid influenza virus vaccine, and another winding is subjected to various IN influenza virus vaccine ingredients.
At the 0th, 21 and 42 day the brown Norway Mus is selected the various ingredients of inoculation.Got serum sample at the 21st, 35 and 56 day, got nasal wash at the 56th day, wash vaginal secretion and BAL.
Each vaccination regimen and Ab reaction are summarized in table 3A-3G.These data show:
It is stronger than the serum influenza Ab titre that causes with DNA or virus inoculation separately that DNA basic vaccination+influenza virus adds strong virus.
IN SFD/ chitosan DNA basic vaccination+IM virus booster shot reacts stronger than the nose IgA that causes with DNA or IM virus inoculation separately.
IN SFD/ chitosan DNA basic vaccination+IM virus booster shot is stronger than the nose IgA reaction that IN FD/ chitosan DNA basic vaccination+booster shot of IM virus causes.
IN SFD/ chitosan DNA basic vaccination+IM virus booster shot is stronger than the nose IgA reaction that the scheme of the same race without chitosan causes.
IN SFD/ chitosan DNA basic vaccination+IM virus booster shot is stronger than the nose IgA reaction that IN liquid dna basic vaccination+booster shot of IM virus causes.
In the BAL of all groups liquid, all detect positive IgA and total Ig titre.
Table 3 is depicted as the trial of influenza dna fundamental immunity+viral booster immunization.Table 3A is depicted as influenza dna fundamental immunity and booster immunization test: the first hemorrhage serum total Ig titre (the 21st day).Table 3B is depicted as influenza dna fundamental immunity and booster immunization test: the second hemorrhage serum total Ig titre (the 35th day).Table 3C is depicted as influenza dna fundamental immunity and booster immunization test: the 3rd hemorrhage serum total Ig titre (the 56th day).Table 3D is depicted as influenza fundamental immunity and booster immunization test: nose IgA titre (the 56th day).Table 3E is depicted as influenza fundamental immunity and booster immunization test: sheath IgA titre (the 56th day).Table 3F is depicted as influenza fundamental immunity and booster immunization test: the total IgA titre of BAL (the 56th day).
As show shown in the 3A-3C, the powder group in this research can cause stronger serum Ab titre than liquid group generally.In addition, the strong nose IgA reaction that IN SFD/ chitosan basis immunity+IM booster immunization (table 3D 5a group) causes is beat all, because no matter be separately with dna immunization or use the IM virus immunity separately, what cause all is that positive nose IgA reacts.IN SFD DNA/ chitosan basis immunity+IM booster immunization is stronger than IN DNA or the independent immunoreation that causes of IM viral vaccine.
Table 3A
| Group | Group 1 | Group 2 | Group 3 | Group 4 | Group 5 |
| Immunity (DNA) | IN liquid | ????IN?FD | ??IN?SFD | IN FD/ chitosan | IN SFD/ chitosan |
| Mus 1 | ??＜50 | ????6400 | ??51200 | ????6400 | ???6400 |
| Mus 2 | ??＜50 | ????12800 | ??12800 | ????3200 | ???25600 |
| Mus 3 | ??1600 | ????6400 | ??25600 | ????6400 | ???6400 |
| Mus 4 | ??400 | ????6400 | ??12800 | ????25600 | ???25600 |
| Mus 5 | ??＜50 | ????800 | ??6400 | ????25600 | ???3200 |
| Mus 6 | ??＜50 | ????25600 | ??6400 | ????12800 | ???3200 |
| Mus 7 | ??800 | ????25600 | ??12800 | ????12800 | ???12800 |
| Mus 8 | ??＜50 | ????12800 | ??12800 | ????6400 | ???25600 |
| Mus 9 | ??200 | ????12800 | ??12800 | ????3200 | ???25600 |
| Mus 10 | ??＜50 | ????12800 | ??12800 | ????12800 | ???3200 |
| Average titer | ??300 | ????12240 | ??16640 | ????11520 | ???13760 |
Table 3B
| Group | Group |
| 1 | | | Group 4 | Group 5 | |
| | IN liquid | ?IN?FD | ??IN?SFD | IN FD/ chitosan | IN SFD/ |
| Mus | |||||
| 1 | ??400 | ?12800 | ??102400 | Dead | ????12800 |
| | ??400 | ?51200 | ??12800 | ????12800 | ????25600 |
| | ??1600 | ?6400 | ??25600 | ????51200 | ????12800 |
| Mus 4 | ??＜50 | ?25600 | ??25600 | ????51200 | ????51200 |
| Mus 5 | ??200 | ?1600 | ??25600 | ????6400 | ????3200 |
| Mus 6 | ??50 | ?25600 | ??51200 | ????51200 | Dead |
| Mus 7 | ??3200 | ?12800 | ??102400 | ????12800 | ????25600 |
| Mus 8 | ??＜50 | ?25600 | ??12800 | Dead | Dead |
| Mus 9 | ??1600 | ?25600 | Dead | ????25600 | |
| Mus | |||||
| 10 | ??200 | ?25600 | ??6400 | ????102400 | ????25600 |
| Average titer | ??765 | ?21280 | ??40533 | ????39200 | ????22400 |
Table 3C
| Group | Group 1A | Group 1B | Group 2A | Group 2B | |
| Immunity | |||||
| 1+2 (DNA) | IN liquid | IN liquid | ??IN?FD | ??IN?FD | ??IN?SFD |
| Immunity 3 (viruses) | ??IM | IN liquid | ??IM | ??IN?FD | ?? |
| Mus | |||||
| 1 | ??51200 | ??25600 | ??409600 | ??819200 | ??819200 |
| | ??25600 | ??102400 | ??819200 | ??819200 | ??819200 |
| | ??819200 | ??25600 | ??819200 | ??819200 | ??819200 |
| Mus 4 | ??51200 | ??409600 | ??409600 | ??819200 | |
| Mus 5 | ??102400 | ??12800 | ??409600 | ??819200 | ??819200 |
| Mus 6 | ??819200 | ||||
| Average titer | ??249600 | ??43520 | ??573440 | ??737280 | ??819200 |
Table 3C (continuing)
| Group | Group 3B | Group 4A | Group 4B | Group 5A | |
| Immunity | |||||
| 1+2 (DNA) | ?IN?SFD | IN FD/ chitosan | IN FD/ chitosan | IN SFD/ chitosan | IN SFD/ chitosan |
| Immunity 3 (viruses) | ?IN?SFD | ??IM | IN FD/ chitosan | ??IM | IN SFD/ |
| Mus | |||||
| 1 | ?819200 | Dead | ????409600 | ??1638400 | |
| Mus | |||||
| 2 | ?1638400 | ??1638400 | ????409600 | ??1638400 | ????204800 |
| | Dead | ??3276800 | Dead | ??1638400 | Dead |
| Mus 4 | ?409600 | ??3276800 | ????819200 | ??1638400 | Dead |
| Mus 5 | ??819200 | ????819200 | ??819200 | ????102400 | |
| Mus 6 | |||||
| Average titer | ?955733 | ??2252800 | ????614400 | ??1474560 | ????153600 |
Table 3D
| Group | Group 1A | Group 1B | Group 2A | Group 2B | |
| Immunity | |||||
| 1+2 (DNA) | IN liquid | IN liquid | ????IN?FD | ????IN?FD | ????IN?SFD |
| Immunity 3 (viruses) | ??IM | IN liquid | ????IM | ????IN?FD | ???? |
| Mus | |||||
| 1 | ??＜10 | ??20 | ????＜10 | ????40 | ????＜10 |
| | ??＜10 | ??40 | ????＜10 | ????40 | ????＜10 |
| | ??＜10 | ??40 | ????＜10 | ????20 | ????＜10 |
| Mus 4 | ??＜10 | ??20 | ????＜10 | ????40 | ????＜10 |
| Mus 5 | ??＜10 | ??＜10 | ????＜10 | ????40 | ????＜10 |
| Mus 6 | ????＜10 | ||||
| Average titer | ??＜10 | ??24 | ????＜10 | ????36 | ????＜10 |
Table 3D (continuing)
| Group | Group 3B | Group 4A | Group 4B | Group 5A | |
| Immunity | |||||
| 1+2 (DNA) | ????IN?SFD | IN FD/ chitosan | IN FD/ chitosan | IN SFD/ chitosan | IN SFD/ chitosan |
| Immunity 3 (viruses) | ????IN?SFD | ????IM | IN FD/ chitosan | ????IM | IN SFD/ |
| Mus | |||||
| 1 | ????160 | Dead | ????40 | ????10 | |
| Mus | |||||
| 2 | ????40 | ????＜10 | ????10 | ????40 | ????40 |
| | Dead | ????＜10 | Dead | ????40 | Dead |
| Mus 4 | ????40 | ????＜10 | ????40 | ????20 | Dead |
| Mus 5 | ????＜10 | ????20 | ????＜10 | ????80 | |
| Mus 6 | |||||
| Average titer | ????80 | ????＜10 | ????27.5 | ????22 | ????60 |
Table 3E
| Group | Group 1A | Group 1B | Group 2A | Group 2B | |
| Immunity | |||||
| 1+2 (DNA) | IN liquid | IN liquid | ????IN?FD | ????IN?FD | ????IN?SFD |
| Immunity 3 (viruses) | ????IM | IN liquid | ????IM | ????IN?FD | ???? |
| Mus | |||||
| 1 | ????＜8 | ????＜8 | ????＜8 | ????＜8 | ????16 |
| | ????＜8 | ????＜8 | ????＜8 | ????＜8 | ????＜8 |
| | ????＜8 | ????＜8 | ????＜8 | ????＜8 | ????＜8 |
| Mus 4 | ????＜8 | ????＜8 | ????＜8 | ????＜8 | ????＜8 |
| Mus 5 | ????＜8 | ????＜8 | ????＜8 | ????＜8 | ????＜8 |
| Mus 6 | ????＜8 |
Table 3E (continuing)
| Group | Group 3B | Group 4A | Group 4B | Group 5A | |
| Immunity | |||||
| 1+2 (DNA) | ????IN?SFD | IN FD/ chitosan | IN FD/ chitosan | IN SFD/ chitosan | IN SFD/ chitosan |
| Immunity 3 (viruses) | ????IN?SFD | ????IM | IN FD/ chitosan | ????IM | IN SFD/ |
| Mus | |||||
| 1 | ????＜8 | Dead | ????＜8 | ????＜8 | |
| Mus | |||||
| 2 | ????＜8 | ????＜8 | ????＜8 | ????＜8 | ????＜8 |
| | Dead | ????＜8 | Dead | ????＜8 | Dead |
| Mus 4 | ????＜8 | ????＜8 | ????＜8 | ????＜8 | Dead |
| Mus 5 | ????＜8 | ????＜8 | ????＜8 | ????＜8 | |
| Mus 6 |
Table 3F
| Group | Group 1A | Group 1B | Group 2A | Group 2B | |
| Immunity | |||||
| 1+2 (DNA) | IN liquid | IN liquid | ????IN?FD | ????IN?FD | ????IN?SFD |
| Immunity 3 (viruses) | ????IM | IN liquid | ????IM | ????IN?FD | ???? |
| Mus | |||||
| 1 | ????4 | ????4 | ????4 | ????16 | ????64 |
| | ????＜1 | ????4 | ????4 | ????4 | ????4 |
| | ????2 | ????32 | ????＜1 | ????4 | ????4 |
| Mus 4 | ????＜1 | ????16 | ????＜1 | ????4 | ????＜1 |
| Mus 5 | ????2 | ????4 | ????2 | ????2 | ????2 |
| Mus 6 | ????32 |
Table 3F (continuing)
| Group | Group 3B | Group 4A | Group 4B | Group 5A | |
| Immunity | |||||
| 1+2 (DNA) | ????IN?SFD | IN FD/ chitosan | IN FD/ chitosan | IN SFD/ chitosan | IN SFD/ chitosan |
| Immunity 3 (viruses) | ????IN?SFD | ????IM | IN FD/ chitosan | ????IM | IN SFD/ |
| Mus | |||||
| 1 | ????32 | Dead | ????16 | ????16 | |
| Mus | |||||
| 2 | ????16 | ????4 | ????＜1 | ????32 | ????8 |
| | Dead | ????2 | Dead | ????4 | Dead |
| Mus 4 | ????16 | ????16 | ????16 | ????16 | Dead |
| Mus 5 | ????4 | ????＜1 | ????4 | ????8 | |
| Mus 6 |
Table 3G
| Group | Group 1A | Group 1B | Group 2A | Group 2B | |
| Immunity | |||||
| 1+2 (DNA) | IN liquid | IN liquid | ????IN?FD | ????IN?FD | ????IN?SFD |
| Immunity 3 (viruses) | ????IM | IN liquid | ????IM | ????IN?FD | ???? |
| Mus | |||||
| 1 | ????64 | ????32 | ????256 | ????256 | ????4096 |
| | ????32 | ????128 | ????256 | ????256 | ????2048 |
| | ????256 | ????32 | ????256 | ????512 | ????256 |
| Mus 4 | ????8 | ????64 | ????256 | ????128 | ????512 |
| Mus 5 | ????64 | ????8 | ????64 | ????256 | ????128 |
| Mus 6 | ????1024 | ||||
| Average titer | ????85 | ????53 | ????218 | ????282 | ????1344 |
Table 3G (continuing)
| Group | Group 3B | Group 4A | Group 4B | Group 5A | |
| Immunity | |||||
| 1+2 (DNA) | ????IN?SFD | IN FD/ chitosan | IN FD/ chitosan | IN SFD/ chitosan | IN SFD/ chitosan |
| Immunity 3 (viruses) | ????IN?SFD | ????IM | IN FD/ chitosan | ????IM | IN SFD/ |
| Mus | |||||
| 1 | ????128 | Dead | ????128 | ????512 | |
| Mus | |||||
| 2 | ????1024 | ????256 | ????32 | ????1024 | ????256 |
| | ????256 | Dead | ????128 | Dead | |
| Mus 4 | ????512 | ????1024 | ????128 | ????1024 | Dead |
| Mus 5 | ????512 | ????256 | ????512 | ????32 | |
| Mus 6 | |||||
| Average titer | ????555 | ????512 | ????136 | ????640 | ????144 |
The insulin of embodiment 9 usefulness SD and the preparation of SFD method and the insulin that contains excipient
What table 4 had been summed up measuring is the spraying-drying of excipient and the physical property of spraying-freeze-dried analgesic composition with the lactose.In the forming process of these compositionss, from the outlet temperature of the solution of nebulizer ejection with particulate yield percentage and bulk density (g/cm
3) detected together.Sample and data list are as follows:
Table 4
| Solution | Process | Bulk density (g/cm 3) |
| Purified insulin | Spray drying | ????0.29 |
| 40/60: insulin/lactose | Spray drying | ????0.49 |
| Purified insulin | Atomizing freeze drying (SFD) | ????0.01 |
| 40/60: insulin/lactose | Atomizing freeze drying (SFD) | ????0.06 |
It is as shown in the table, and the bulk density of 40/60 solution of the purified insulin of atomizing freeze drying and insulin/lactose is significantly less than spray-dired insulin and insulin/lactose granule.The SFD powder composition can keep protein stability and biological activity better than spray-dried compositions.On the contrary, spray-dired purified insulin and insulin/lactose (40/60) powder is obviously more closely knit, and bulk density is 0.29 and 0.49g/cm
3Though do not want to be subjected to the constraint of any particular theory, the present patent application people believes why have these advantages to be because the conventional spraying-baking temperature of temperature ratio that spraying-freeze-dried takes place low (low 100 ℃ approximately).
With spraying-freeze-dried of the present invention (dry freeze) method processing 2wt% insulin solution and 5wt% insulin/lactose (40/60), the gained porous particle has aerocolloidal character, is fit to be transported in the respiratory system of animal.
Applicant's test shows, the minimum aerodynamic particle diameter that obtains with the atomizing freeze drying method is the insulin that does not contain excipient, promptly is the particle diameter of the insulin of pure substance basically.But, should be appreciated that by insulin and excipient and form but the ingredients that can satisfy with the purpose of respiratory system administration is also included within the scope of the invention.In addition, compare with spray drying insulin/lactose granule, SFD insulin granule (Figure 19) is exposed to common temperature damp condition (20 ℃ 53%RH) after following 15 minutes, and are nearly all detected generation less than hydration in storage.Otherwise Figure 20 has shown that SFD insulin/lactose granule is exposed to the form that identical common temperature damp condition is kept after following 15 minutes.Usually, SFD insulin/lactose granule be exposed to＞50% relative humidity following time will absorb the moisture of 2-5wt% at least.These results show, compare with SFD porous insulin/lactose, and the SFD porous insulin for preparing with the inventive method has higher resistance to common dampness.
The powder that remains in the conveyer device after another speciality that the inventive method has is to use greatly reduces.The percent dose that the particular delivery device is taken in can be calculated by weight.For example, API prepared according to the methods of the invention, when using with the 09/758776 described conveyer device that is registered in January 12 calendar year 2001 by the U.S. Patent application 09/879517 that is registered in June 12 calendar year 2001, powder residual in conveyer device is less than 5%.As a comparison, the spray-dried powders that remains in the conveyer device of the same race is about 20wt%.In addition, can observe by naked eyes, it is very high that the SFD powder forms aerocolloidal process efficiency, do not have residual powder in the respiratory system conveyer device basically.After the medicament carrier capsule that includes SD (lower-left capsule) and SFD (upper right capsule) powder takes out from this device, the breakable capsule film, its photo is shown in Figure 21, and this figure has clearly showed the aerosol character of SFD powder excellence.
The stability of embodiment 10 SFD insulin powder and liquid insulin relatively
Mensuration has also compared SFD insulin and the stability that contains the U500 liquid Lilly Humulin-R of metacresol, and the latter is current widely used normal fluid insulin.SFD purified insulin and insulin/trehalose measured for 8 weeks under 40 ℃ and 75% humidity.Measured the purified insulin that is sealed in the aluminum packing equally.The liquid insulin is measured under 25 ℃ (room temperatures) and 60% relative humidity.Measure the percentage ratio of the amide of formation, determine each stability of sample thus with respect to sample.The formation percent of amide at the beginning, 1 week, 2 weeks, 4 weeks, 6 weeks and measured in 8 weeks.
Known amide can produce immunity to insulin in patient's body, so diabetics is had harmful effect.FDA regulation insulin lactams content must be lower than 10%.
Experiment showed, that the SFD purified insulin is all especially stable in the mensuration in whole 8 weeks.The measurement result of SFD purified insulin is:
In 1 week of beginning in 6 all 8 weeks of 4 weeks in 2 weeks
SFD purified insulin sample with the aluminum parcel shows chemical stability at whole 8 all test periods.Up to the 6th week, the amount of detected amide is lower than statistical error, thereby can ignore.The detection peak of amide occurred in the 6th week, was 0.75%.Measurement result with the SFD purified insulin of aluminum parcel is as follows:
In 1 week of beginning in 6 all 8 weeks of 4 weeks in 2 weeks
The SFD insulin that with the trehalose is excipient also obtains measuring.In this case, just detect amide up to the 6th week.On the whole, add the preservation life-span that trehalose has obviously improved the SFD insulin.
The result is as follows:
In 1 week of beginning in 6 all 8 weeks of 4 weeks in 2 weeks
% amide 0000 0.24 1.57
The reference fluid insulin was measured for 8 weeks equally, to determine the recruitment of amide.Experiment shows that in 8 all test periods, the stability of liquid insulin is more far short of what is expected than SFD insulin.Except measuring, also measured the liquid insulin at the 24th and 72 hour by week.In these early stage mensuration, do not detect the increase of amide.Measure under the condition of storage that but a remarkable parameter of this research is the liquid insulin a little less than than the SFD insulin Duos.In addition, the liquid insulin contains the chemical preservative metacresol, in order to slow down the increase of amide.
In 1 week of beginning in 6 all 8 weeks of 4 weeks in 2 weeks
Experiment shows that each SFD insulin sample is all much stable than the liquid insulin.The liquid insulin is obviously more faster than the degraded of SFD powder.With the SFD insulin of aluminum parcel is under 40 ℃ and 75% relative humidity condition, the most stable sample in 8 all minutes.The result shows that the SFD powdered insulin is much more stable than present commercial liquid insulin ingredients.
Figure 10 has shown that the amide of SFD purified insulin and liquid insulin advances the speed.
Embodiment 11 vibrated fluidized bed atomizing freeze dryings
Introduce in other places as this description, in the presence of internals and vibration component, under near normal pressure (antivacuum), can successfully prepare the porous particle of spraying-freeze-dried.Experiment shows that the fluid mapper process under internals and vibration component help can promote freezing aerocolloidal distillation.In less than 40 minutes time, under-20 ℃, 20wt% mannitol solution (Figure 11) (promptly containing 80wt% moisture) is dried to 0.3wt%.This is better than the result that Leuenberger (USP 4608764) etc. obtains.
The moisture of 20wt% mannitol and drying time, (as the function of dry gas speed) was shown in Figure 11.The minimum drying curve that presents in the table produces in BDT, and other data are then selected from document Leuenberger (USP 4608764).From TGA result, after under the gas velocity of 2m/s dry 40 minutes, residual moisture is about 0.3%.SEM among Figure 12 shows that granule has the porous form.In spray chilling aerosol, have strong adhesive power between granule and the fluidized gas, thereby be easy to pass fluid bed and upwards form channel less than 20 μ m.Dry and during not by internals and vibration component under 0.39m/s ,-20 ℃ of conditions when the spray chilling powder, the powder of finding 95wt% after dry 3 hours is owing at the bottom of channel is retained in bed.Channel in the fluid bed makes the drying effect variation.The powder elutriation of about 5wt% is (after dry 3 hours) to bed top, and its dry rate is more faster than the powder at the bottom of being collected in bed.The elutriation process is, when gas superficial speed is higher than granule/agglomerate tail speed, fluidized gas just with the fine grained band from fluid bed.Embodiment 12 has explained dry gas speed and elutriation effect in the fluid bed by analysis of mass transfer.Figure 14 shows that in the humidity of each time point at the sample of bed top and the collection of the bed end.Has only 5% spray chilling powder elutriation to the drying bed top.At the bottom of 95% freezing powder is retained in bed; The drying efficiency difference is attributable to channel.Elutriation is taken a sample at the 30th and 60 minute to the powder (collecting with filter disc) on bed top, and its SEM figure sees Figure 15 and 16.The powder for drying that the powder of collecting in the 60th minute was collected unlike the 30th minute.After sample took out, the new elutriation exsiccant powder of part that comes out was sneaked in the more exsiccant powder, causes particulate reunion.Under internals and vibration component help, all elutriations form uniform cake to the powder on fluid bed top, therefore eliminated channel and efficient drying is provided.As shown in figure 17, under the higher dry gas speed of 2m/s, 20wt% mannitol is dried to the speed of voluminous powder (0.3wt% is surplus wet) than faster under the low dry gas speed of 0.39m/s.Figure has shown in vibrated fluidized bed SFD process, flow velocity and distillation time relation.In the presence of vibration component and internals, all powder elutriation is to the drying bed top.High flow rate makes drying faster, so drying efficiency is also higher.
The analysis of mass transfer of dry run in embodiment 12 fluid beds and the fixed bed drying device
The particulate final sedimentation rate of 20 μ m is about 0.012m/s (speed=ρ
pd
p 2G/18 μ), it is corresponding to the single frozen particle in the elutriation process.Under so low gas flow rate (low reynolds number), mass tranfer coefficient is very low.Richardson and Szekely (1961) have set up following empirical equation, and mass tranfer coefficient k and Reynolds number in the gas-solid fluidized bed are associated.
Sh＝0.37R
e 1.8??0.1＜Re＜15，
Wherein Sh is sherwood number (=kd
p/ D), k is a mass tranfer coefficient, D is a diffusion coefficient, d
pBe particle diameter, Re is Reynolds number (=ρ
pUd
p/ μ).If the particulate mass size is d
a=200 μ m, density of nitrogen is 1.29kg/m
3, nitrogen flow rate is 1.81 * 10
-5Kg/m/s (Pa*s), fluid rate are 0.012m/s (20 μ m individual particle tail speed.If fluidized gas speed is higher than individual particle tail speed, because the agglomerate in the fluid bed collides and fricative individual particle will be pulled away or elutriation is come out), (Re=0.171), then Sh is 1.54 * 10
-2
When dry gas speed is higher than 0.012m/s, granule (20 μ m or littler) will go out from the fluid bed elutriation, need collect with filter or cyclone separator.All outside granule tail speed, filter disc is collected powder in the process of the freezing powder of cold dry gas stream continuous drying in the operation of Leuenberger and BDT.As a result, coming out in the elutriation of fluid bed top exit in clammy agar end, forms even cake.Out-of-date when the dry gas high velocity stream, dry run is similar to the fixed bed drying device.The mass transport process of fixed bed also can be passed through Ranz (1952) at Chem.Eng.Prog.48, and another empirical equation that proposes in 247 calculates:
Sh＝2.0+1.8Sc
1/3Re
1/2
Wherein, Sc is Schmidt number (=μ/ρ
gD).When Re was higher, for example working as particle diameter was 20 μ m, and density of nitrogen is 1.29kg/m
3, nitrogen viscosity is 1.81 * 10
-5Kg/m/s, fluid rate are 2.0m/s (be 60 liters/minute, source nitrogen pressure is 40psi) in our experiment, and then Sh is 4.7 as calculated.By the mass transport process between gas and the solid in relatively lower Re fluid bed and the high Re fixed bed, can draw two kinds of mass transfer ratios under the situation and be about 1: 300.
In one group of experiment, drying nitrogen speed is 0.03m/s, is used for dry 5wt%PEG solution (95% moisture).Under this flow velocity, some powder elutriate (collecting with filter paper) are arranged.But, on filter paper, do not observe " powder ", because these frozen particles bone dry has not as yet thawed again in the time of on depositing to filter paper.The freezing sample of collecting at the bottom of bed after 4 hours of fluidisation (real fluidisation) still contains 93% moisture.This observed result is supported our sherwood number analysis, and promptly fluid mapper process is slow, mass transfer (drying) speed difference.
According to above description, those skilled in the art are easy to determine basic feature of the present invention.Under the prerequisite that does not deviate from original intention of the present invention and scope, can make various changes and modifications to the present invention, to adapt to various uses and condition.
Need not to give unnecessary details, we believe the description of those skilled in the art by the front, can utilize the present invention fullest.Therefore, the preferred implementation of preceding mask body can only be interpreted as exemplary, rather than to any restriction of other situations of the present invention.
Above with accompanying drawing in all applications, patent and the document quoted, its full content is hereby incorporated by reference.
Claims (56)
1. with a kind of pharmaceutical composition of method preparation, described method comprises:
Nebulae inhalation disease or prophylactic liquid ingredients produce the atomizing ingredients;
Freezing described atomizing ingredients forms solid granulates;
Dry described solid granulates forms dried particles,
The volume mean diameter of wherein said dried particles between 35-300 μ m, the volume diameter of 50% the dried particles of wherein having an appointment at least average diameter about 80% within, the average air power diameter of described dried particles is between about 8-140 μ m.
2. the described pharmaceutical composition of claim 1, the volume mean diameter that it is characterized in that described dried particles is between 50-300 μ m.
3. the described pharmaceutical composition of claim 1, the volume mean diameter that it is characterized in that described dried particles is between 50-100 μ m.
4. the described pharmaceutical composition of claim 1, the average air power diameter that it is characterized in that described dried particles is between about 20-70 μ m.
5. the described pharmaceutical composition of claim 1, it is characterized in that described freezing by being lower than fluid from described liquid formulation freezing point to temperature or medium in introduce described atomizing ingredients and carry out.
6. the described pharmaceutical composition of claim 5 is characterized in that the boiling point of described fluid or medium or boiling point or the sublimation point that sublimation point is lower than described atomizing ingredients.
7. the described pharmaceutical composition of claim 5 is characterized in that described fluid is a gas.
8. the described pharmaceutical composition of claim 5 is characterized in that described fluid is a liquid.
9. the described pharmaceutical composition of claim 1 is characterized in that described granule is by the dry freeze drying.
10. the described pharmaceutical composition of claim 1 is characterized in that described granule near under the normal pressure, and is dry in the presence of vibration component, internals, mechanical agitation member or their combinations.
11. the described pharmaceutical composition of claim 10 is characterized in that described dried particles is further by the dry freeze drying.
12. the described pharmaceutical composition of claim 1 is characterized in that described therapeutic agent is protein, nucleic acid or virion.
13. the described pharmaceutical composition of claim 1 is characterized in that described therapeutic agent is an immunoreagent.
14. the described pharmaceutical composition of claim 13 is characterized in that described immunoreagent is influenza vaccines.
15. the described pharmaceutical composition of claim 14 is characterized in that described influenza vaccines comprise inactivating influenza virus granule or nucleic acid coding influenza hemagglutinin protein matter, it effectively is connected with the CMV promoter.
16. the described pharmaceutical composition of claim 1 is characterized in that described therapeutic agent is an insulin.
17. the described pharmaceutical composition of claim 1 is characterized in that described liquid formulation comprises mucoadhesive.
18. the described pharmaceutical composition of claim 17 is characterized in that described mucoadhesive is chitosan, dermatan sulfate, chrondroitin or pectin.
19. the described pharmaceutical composition of claim 1 is characterized in that described liquid formulation mainly is made up of therapeutic agent and water.
20. the pharmaceutical composition by following method preparation: nebulae inhalation disease or prophylactic liquid ingredients produce the atomizing ingredients; Freezing described atomizing ingredients forms solid granulates; Dry described solid granulates, form dried particles, the volume mean diameter of described dried particles is between 35-300 μ m, wherein have an appointment at least 50% dried particles volume diameter average diameter about 80% within, the average air power diameter of described dried particles is between about 8-140 μ m.
21. comprise the pharmaceutical composition of dried particles and pharmaceutical carrier, the average air power diameter that it is characterized in that described dried particles is between about 8-140 μ m, volume mean diameter between 35-300 μ m, the volume diameter of 50% the dried particles of wherein having an appointment at least average diameter about 80% within.
22. with a kind of pharmaceutical composition of method preparation, described method comprises:
Nebulae inhalation disease or prophylactic liquid ingredients produce the atomizing ingredients, and described atomizing ingredients comprises the droplet of volume mean diameter between 35-300 μ m;
Freezing described atomizing ingredients forms solid granulates;
Dry described solid granulates forms dried particles,
The volume mean diameter of wherein said dried particles between 35-300 μ m, the volume diameter of 50% the dried particles of wherein having an appointment at least average diameter about 80% within, the average air power diameter of described dried particles is between about 8-140 μ m.
23. the method for a pharmaceutical compositions, described method comprises:
Nebulae inhalation disease or prophylactic liquid ingredients produce the atomizing ingredients;
Freezing described atomizing ingredients forms solid granulates;
Dry described solid granulates forms dried particles,
The volume mean diameter of wherein said dried particles between 35-300 μ m, the volume diameter of 50% the dried particles of wherein having an appointment at least average diameter about 80% within, the average air power diameter of described dried particles is between about 8-140 μ m.
24. the described method of claim 23, the volume mean diameter that it is characterized in that described dried particles is between 50-300 μ m.
25. the described method of claim 23, the volume mean diameter that it is characterized in that described dried particles is between 50-100 μ m.
26. the described method of claim 23, the average air power diameter that it is characterized in that described dried particles is between about 20-70 μ m.
27. the described method of claim 23, it is characterized in that described freezing by being lower than fluid from described liquid formulation freezing point to temperature or medium in introduce described atomizing ingredients and carry out.
28. the described method of claim 27 is characterized in that the boiling point of described fluid or medium or boiling point or the sublimation point that sublimation point is lower than described atomizing ingredients.
29. the described method of claim 27 is characterized in that described fluid is a gas.
30. the described method of claim 27 is characterized in that described fluid is a liquid.
31. the described method of claim 23 is characterized in that described granule is by the dry freeze drying.
32. the described method of claim 23 is characterized in that described granule near under the normal pressure, and is dry in the presence of vibration component, internals, mechanical agitation member or their combinations.
33. the described method of claim 23 is characterized in that described drying unites near under the normal pressure drying and dry freeze drying in the presence of vibration component, internals, mechanical agitation member or their combinations.
34. the described method of claim 23, described therapeutic agent are protein, nucleic acid or virion.
35. the described method of claim 23 is characterized in that described therapeutic agent is an immunoreagent.
36. the described method of claim 35 is characterized in that described immunoreagent is influenza vaccines.
37. the described method of claim 36 is characterized in that described influenza vaccines comprise inactivating influenza virus granule or nucleic acid coding influenza hemagglutinin protein matter, it effectively is connected with the CMV promoter.
38. the described method of claim 23 is characterized in that described therapeutic agent is an insulin.
39. the described method of claim 23 is characterized in that described liquid formulation comprises mucoadhesive.
40. the described method of claim 39 is characterized in that described mucoadhesive is chitosan, dermatan sulfate, chrondroitin or pectin.
41. the described method of claim 23 is characterized in that described liquid formulation mainly is made up of therapeutic agent and water.
42. the method for a pharmaceutical compositions, described method comprises: nebulae inhalation disease or prophylactic liquid ingredients produce the atomizing ingredients; Freezing described atomizing ingredients forms solid granulates; Dry described solid granulates, form powder, described powder comprises the dried particles of volume mean diameter between 35-300 μ m, wherein have an appointment at least 50% dried particles volume diameter average diameter about 80% within, the average air power diameter of described dried particles is between about 8-140 μ m.
43. a Therapeutic Method, it comprises the described pharmaceutical composition of claim 1 of using effective dose to the patient that demand is arranged.
44. the described method of claim 43, it is characterized in that described compositions by in the respiratory system, intranasal, internal rectum, intravaginal, Sublingual or parenteral administration.
45. the described method of claim 43 is characterized in that described compositions dispenser to nasal mucosa.
46. a Therapeutic Method, it comprises the described pharmaceutical composition of claim 20 of using effective dose to the patient that demand is arranged.
47. a Therapeutic Method, it comprises the described pharmaceutical composition of claim 10 of using effective dose to the patient that demand is arranged.
48. a method that reduces the therapeutic agent consumption, described consumption are that this method comprises the described pharmaceutical composition of claim 1 of using effective dose by intranasal to the patient to the required dosage of generation curative effect behind patient's Nasacort.
49. in patient's body, cause immunoreactive method, comprise the described immune composition of claim 13 of using effective dose to described patient.
50. the described method of claim 49 is characterized in that described compositions passes through intranasal administration.
51. the described method of claim 50 is characterized in that described immune composition is influenza vaccines.
52. the described method of claim 51 is characterized in that described influenza vaccines comprise inactivating influenza virus granule or nucleic acid coding influenza hemagglutinin protein matter, it effectively is connected with the CMV promoter.
53. the described method of claim 51 is characterized in that described influenza vaccines comprise inactivating influenza virus granule or influenza virus subunit.
54. the described method of claim 49 is characterized in that described immune composition uses as the part of basis-reinforcement course of treatment.
55. the described method of claim 54 is characterized in that using described immune composition in the fundamental immunity, uses virus formulation in the booster immunization.
56. the described method of claim 54 is characterized in that fundamental immunity passes through intranasal administration, booster immunization is by the muscle administration.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33195201P | 2001-11-19 | 2001-11-19 | |
| US60/331,952 | 2001-11-19 | ||
| US33915601P | 2001-12-11 | 2001-12-11 | |
| US60/339,156 | 2001-12-11 | ||
| US41995902P | 2002-10-22 | 2002-10-22 | |
| US60/419,959 | 2002-10-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1607941A true CN1607941A (en) | 2005-04-20 |
Family
ID=27406830
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028260074A Pending CN1607941A (en) | 2001-11-19 | 2002-11-19 | Pharmaceutical compositions in particulate form |
| CNB028262204A Expired - Fee Related CN1287770C (en) | 2001-11-19 | 2002-11-19 | Pharmaceutical compositions in particulate form |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028262204A Expired - Fee Related CN1287770C (en) | 2001-11-19 | 2002-11-19 | Pharmaceutical compositions in particulate form |
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|---|---|
| US (3) | US7842310B2 (en) |
| EP (2) | EP1455754A4 (en) |
| JP (2) | JP2005532987A (en) |
| KR (2) | KR20050044523A (en) |
| CN (2) | CN1607941A (en) |
| AU (2) | AU2002346424A1 (en) |
| BR (2) | BR0214280A (en) |
| CA (2) | CA2466982A1 (en) |
| MX (2) | MXPA04004726A (en) |
| WO (2) | WO2003072016A2 (en) |
| ZA (1) | ZA200403848B (en) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102830222A (en) * | 2012-09-20 | 2012-12-19 | 成都斯马特科技有限公司 | Method for preparing solid granular biochemical reagent |
| CN104198717A (en) * | 2014-08-30 | 2014-12-10 | 中国科学院苏州生物医学工程技术研究所 | Freeze-drying concentrated glucose detection reagent microsphere and preparation method thereof |
| CN104198717B (en) * | 2014-08-30 | 2016-04-06 | 中国科学院苏州生物医学工程技术研究所 | A kind of concentrated glucose determination reagent freeze-drying microballoon and preparation method thereof |
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| CN1287770C (en) | 2006-12-06 |
| US20030186271A1 (en) | 2003-10-02 |
| BR0214279A (en) | 2005-12-20 |
| CA2467833A1 (en) | 2003-09-04 |
| EP1455754A2 (en) | 2004-09-15 |
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| US20070190158A1 (en) | 2007-08-16 |
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| JP2005518430A (en) | 2005-06-23 |
| EP1455754A4 (en) | 2006-01-18 |
| US7842310B2 (en) | 2010-11-30 |
| AU2002346424A1 (en) | 2003-06-10 |
| KR20040073438A (en) | 2004-08-19 |
| EP1458362A2 (en) | 2004-09-22 |
| US20030180755A1 (en) | 2003-09-25 |
| MXPA04004726A (en) | 2004-07-30 |
| WO2003043574A2 (en) | 2003-05-30 |
| EP1458362A4 (en) | 2006-01-18 |
| JP2005532987A (en) | 2005-11-04 |
| AU2002366267B2 (en) | 2007-05-10 |
| BR0214280A (en) | 2005-01-11 |
| KR20050044523A (en) | 2005-05-12 |
| CA2466982A1 (en) | 2003-05-30 |
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